Objective:To reveal the distribution signature of cancer susceptibility genes in patients with gastric adenocarcinoma,offering a diagnostic and prognostic surrogate for disease risk management and therapeutic decision...Objective:To reveal the distribution signature of cancer susceptibility genes in patients with gastric adenocarcinoma,offering a diagnostic and prognostic surrogate for disease risk management and therapeutic decisions.Methods:A total of 282 patients with gastric adenocarcinoma(182 males and 100 females)were enrolled in this study,with peripheral blood genomic DNA extracted.Mutations of 69 canonical cancer susceptibility genes or presumably tumor-related genes were analyzed by targeted capture-based high-throughput sequencing.Candidate mutations were particularly selected for discussion on tumor pathogenesis according to the American College of Medical Genetics and Genomics(ACMG)guidelines.Results:In this study,7.1%(20/282)of patients with gastric adenocarcinoma were found to harbor mutations of canonical or presumable cancer susceptibility genes.The detection rate in male patients(3.8%,7/182)was significantly lower than that in female patients(13%,13/100)(P=0.004).The most recurrent mutations were in AT mutated(ATM)(1.1%,3/282),followed by BRCA1,BRIP1 and RAD51D,all showed a detection rate of 0.7%(2/282).Mutations in three genes associated with hereditary gastric cancer syndromes were detected,namely,PMS2 and EP CAM associated with Lynch syndrome and CDH1 associated with hereditary di ffuse gastric cancer.The detection frequencies were all 0.4%(1/282).Notwithstanding no significant difference observed,the age of patients with pathogenic mutations or likely pathogenic mutations is slightly younger than that of non-carriers(median age:58.5 vs.60.5 years old),while the age of patients with ATM mutations was the youngest overall(median age:49.3 years old).Conclusions:Our study shed more light on the distribution signature and pathogenesis of mutations in gastric cancer susceptibility genes,and found the detection rate of pathogenic and likely pathogenic mutations in male patients was significandy lower than that in female patients.Some known and unidentified mutations were found in gastric cancer,which allowed us to gain more insight into the hereditary gastric cancer syndromes from the molecular perspective.展开更多
In accordance with previous reports, the sequences related to phosporylated protein segments occur in conserved variable domains of immunoglobulins including first of all certain N-terminally located segments. Consequ...In accordance with previous reports, the sequences related to phosporylated protein segments occur in conserved variable domains of immunoglobulins including first of all certain N-terminally located segments. Consequently, we look here for the sequences 1) composing human and mouse proteins different from antigen receptors, 2) identical with or highly similar to nucleotide sequence representatives of conserved variable immunoglobulin segments and 3) identical with or closely related to phosphorylation sites. More precisely, we searched for the corresponding actual pairs of DNA and protein sequence segments using five-step bilingual approach employing among others a) different types of BLAST searches, b) two in-principle-different machine-learning methods predicting phosphorylated sites and c) two large databases recording existing phosphorylation sites. The approach identified seven existing phosphorylation sites and thirty-seven related human and mouse segments achieving limits for several predictions or phylogenic parameters. Mostly serines phosporylated with ataxia-telangiectasia-related kinase (involved in regulation of DNA-double-strand-break repair) were indicated or predicted in this study. Hypermutation motifs, located in effective positions of the selected sequence segments, occurred significantly less frequently in transcribed than non-transcribed DNA strands suggesting thus the incidence of mutation events. In addition, marked differences between the numbers and proportions of human and mouse cancer-related sequence items were found in different steps of selection process. The possible role of hypermutation changes within the selected segments and the observed structural relationships are discussed here with respect to DNA damage, carcinogenesis, cancer vaccination, ageing and evolution. Taken together, our data represent additional and sometimes perhaps complementary information to the existing databases of empirically proven phosphorylation sites or pathogenically important spots.展开更多
This study was aimed to identify the mutation of the whole coding region of shock transcription factor 4（HSF4） gene in a Chinese family with autosomal dominant congenital cataract（ADCC）. All exons of HSF4 were amp...This study was aimed to identify the mutation of the whole coding region of shock transcription factor 4（HSF4） gene in a Chinese family with autosomal dominant congenital cataract（ADCC）. All exons of HSF4 were amplified by PCR. Sequence analysis of PCR products was performed. Restriction fragment length polymorphism（RFLP） analysis was conducted to confirm the pathogenic mutation. The results showed that a C to T substitution occurred at nucleotide 331 in patients of this family, leading to the replacement of the amino acid arginine-111 with cysteine in exon 3. RFLP analysis showed that the amino acid change was co-segregated with all affected individuals. It was concluded that the new mutation of c.331C〉T in HSF4 DNA may be responsible for the autosomal dominant congenital cataract in this family.展开更多
BACKGROUND Adenylosuccinate lyase(ADSL)deficiency is a rare autosomal-recessive defect of purine metabolism caused by mutation of the ADSL gene.It can cause severe neurological impairment and diverse clinical manifest...BACKGROUND Adenylosuccinate lyase(ADSL)deficiency is a rare autosomal-recessive defect of purine metabolism caused by mutation of the ADSL gene.It can cause severe neurological impairment and diverse clinical manifestations,including epilepsy.CASE SUMMARY Here,we describe a 3-year-old Chinese boy who had both psychomotor retardation and refractory epilepsy.Magnetic resonance imaging showed myelin hypoplasia.Electroencephalography findings supported a diagnosis of epilepsy.Whole-exon sequencing revealed the presence of a novel complex heterozygous mutation in the ADSL gene:The splicing mutation c.154-3C>G and the missense mutation c.71C>T(p.Pro24Leu).Considering the patient’s clinical presentation and genetic test results,the complex heterozygous mutation was predicted to prevent both ADSL alleles from producing normal ADSL,which may have led to ADSL deficiency.Finally,the child was diagnosed with ADSL deficiency.CONCLUSION We identified a novel complex heterozygous mutation in the ADSL gene associated with ADSL deficiency,thus expanding the known spectrum of pathogenic mutations that cause ADSL deficiency.Additionally,we describe epilepsy that occurs in patients with ADSL deficiency.展开更多
BACKGROUND CYP21A2 gene mutations may all cause reduction or loss of 21-hydroxylase activity,leading to development of congenital adrenal hyperplasia(CAH)with different clinical phenotypes.For families with CAH childr...BACKGROUND CYP21A2 gene mutations may all cause reduction or loss of 21-hydroxylase activity,leading to development of congenital adrenal hyperplasia(CAH)with different clinical phenotypes.For families with CAH children,genetic testing of the parents and genetic counseling are recommended to assess the risk of recurrence.CASE SUMMARY We report a case of CAH with a high suspicion before delivery.The risk of the child suffering from CAH during the pregnancy had been underestimated due to the deviation of genetic counseling and genetic testing results.Our report confirmed a CYP21A2 homozygous deletion in this case,CYP21A2 heterozygous deletion in the mother,and a rare 2+0 CYP21A2 deletion in the father.CONCLUSION It is important to analyze the distribution of CYP21A2 gene in the two alleles of parents of children with CAH.展开更多
Hypertrophic cardiomyopathy(HCM)is one of the most common inherited cardiovascular diseases,with a global prevalence estimated at 0.2%to 0.5%.1 It is characterized by left ventricular hypertrophy which could not be ex...Hypertrophic cardiomyopathy(HCM)is one of the most common inherited cardiovascular diseases,with a global prevalence estimated at 0.2%to 0.5%.1 It is characterized by left ventricular hypertrophy which could not be explained by abnormal loading conditions,and a considerable proportion of patients were accompanied by either resting or inducible left ventricular outflow tract(LVOT)obstruction,leading to impaired cardiac function,mitral regurgitation due to systolic anterior motion(SAM)condition,with subsequent reduced quality of life,adverse clinical outcomes or even sudden death(Supplementary Text 1 online).2 HCM was previously believed to exhibit an autosomal dominant inheritance pattern,typically caused by pathogenic mutations in genes encoding sarcomeric proteins,with MYBPC3 and MYH7 being the most commonly involved genes.3 However,about 60%of all patients test negative for sarcomeric variants,4 suggesting a possible polygenic inheritance pattern in these patients and the contribution of non-genetic factors on disease phenotype(Supplementary Text 2 online).展开更多
In the post-genomic era,a central challenge for disease genomes is the identification of the biological effects of specific somatic variants on allosteric proteins and the phenotypes they influence during the initiati...In the post-genomic era,a central challenge for disease genomes is the identification of the biological effects of specific somatic variants on allosteric proteins and the phenotypes they influence during the initiation and progression of diseases.Here,we analyze more than 38539 mutations observed in 90 human genes with 740 allosteric protein chains.We find that existing allosteric protein mutations are associated with many diseases,but the clinical significance of most mutations in allosteric proteins remains unclear.Next,we develop an ensemble-learning-based model for pathogenic mutation prediction of allosteric proteins based on the intrinsic characteristics of proteins and the prediction results from existed methods.When tested on the benchmark allosteric protein dataset,the proposed method achieves an AUCs of 0.868 and an AUPR of 0.894 on allosteric proteins.Furthermore,we explore the performance of existing methods in predicting the pathogenicity of mutations at allosteric sites and identify potential significant pathogenic mutations at allosteric sites using the proposed method.In summary,these findings illuminate the significance of allosteric mutation in disease processes,and contribute a valuable tool for the identification of pathogenic mutations as well as previously unknown disease-causing allosteric-protein-encoded genes.展开更多
基金This study was supported by Shenzhen Sanming Project(No.SZSM201612051)Shenzhen Science and Technology Innovation Commission Project(No.ZDSYS 20190902092855097,No.GJHZ20180420180754917).
文摘Objective:To reveal the distribution signature of cancer susceptibility genes in patients with gastric adenocarcinoma,offering a diagnostic and prognostic surrogate for disease risk management and therapeutic decisions.Methods:A total of 282 patients with gastric adenocarcinoma(182 males and 100 females)were enrolled in this study,with peripheral blood genomic DNA extracted.Mutations of 69 canonical cancer susceptibility genes or presumably tumor-related genes were analyzed by targeted capture-based high-throughput sequencing.Candidate mutations were particularly selected for discussion on tumor pathogenesis according to the American College of Medical Genetics and Genomics(ACMG)guidelines.Results:In this study,7.1%(20/282)of patients with gastric adenocarcinoma were found to harbor mutations of canonical or presumable cancer susceptibility genes.The detection rate in male patients(3.8%,7/182)was significantly lower than that in female patients(13%,13/100)(P=0.004).The most recurrent mutations were in AT mutated(ATM)(1.1%,3/282),followed by BRCA1,BRIP1 and RAD51D,all showed a detection rate of 0.7%(2/282).Mutations in three genes associated with hereditary gastric cancer syndromes were detected,namely,PMS2 and EP CAM associated with Lynch syndrome and CDH1 associated with hereditary di ffuse gastric cancer.The detection frequencies were all 0.4%(1/282).Notwithstanding no significant difference observed,the age of patients with pathogenic mutations or likely pathogenic mutations is slightly younger than that of non-carriers(median age:58.5 vs.60.5 years old),while the age of patients with ATM mutations was the youngest overall(median age:49.3 years old).Conclusions:Our study shed more light on the distribution signature and pathogenesis of mutations in gastric cancer susceptibility genes,and found the detection rate of pathogenic and likely pathogenic mutations in male patients was significandy lower than that in female patients.Some known and unidentified mutations were found in gastric cancer,which allowed us to gain more insight into the hereditary gastric cancer syndromes from the molecular perspective.
文摘In accordance with previous reports, the sequences related to phosporylated protein segments occur in conserved variable domains of immunoglobulins including first of all certain N-terminally located segments. Consequently, we look here for the sequences 1) composing human and mouse proteins different from antigen receptors, 2) identical with or highly similar to nucleotide sequence representatives of conserved variable immunoglobulin segments and 3) identical with or closely related to phosphorylation sites. More precisely, we searched for the corresponding actual pairs of DNA and protein sequence segments using five-step bilingual approach employing among others a) different types of BLAST searches, b) two in-principle-different machine-learning methods predicting phosphorylated sites and c) two large databases recording existing phosphorylation sites. The approach identified seven existing phosphorylation sites and thirty-seven related human and mouse segments achieving limits for several predictions or phylogenic parameters. Mostly serines phosporylated with ataxia-telangiectasia-related kinase (involved in regulation of DNA-double-strand-break repair) were indicated or predicted in this study. Hypermutation motifs, located in effective positions of the selected sequence segments, occurred significantly less frequently in transcribed than non-transcribed DNA strands suggesting thus the incidence of mutation events. In addition, marked differences between the numbers and proportions of human and mouse cancer-related sequence items were found in different steps of selection process. The possible role of hypermutation changes within the selected segments and the observed structural relationships are discussed here with respect to DNA damage, carcinogenesis, cancer vaccination, ageing and evolution. Taken together, our data represent additional and sometimes perhaps complementary information to the existing databases of empirically proven phosphorylation sites or pathogenically important spots.
基金supported by grants from the National Natural Science Foundation of China(No.81371064 and No.J1103514)
文摘This study was aimed to identify the mutation of the whole coding region of shock transcription factor 4（HSF4） gene in a Chinese family with autosomal dominant congenital cataract（ADCC）. All exons of HSF4 were amplified by PCR. Sequence analysis of PCR products was performed. Restriction fragment length polymorphism（RFLP） analysis was conducted to confirm the pathogenic mutation. The results showed that a C to T substitution occurred at nucleotide 331 in patients of this family, leading to the replacement of the amino acid arginine-111 with cysteine in exon 3. RFLP analysis showed that the amino acid change was co-segregated with all affected individuals. It was concluded that the new mutation of c.331C〉T in HSF4 DNA may be responsible for the autosomal dominant congenital cataract in this family.
基金Supported by the Natural Science Foundation of Shandong Province,No.ZR2019MH060。
文摘BACKGROUND Adenylosuccinate lyase(ADSL)deficiency is a rare autosomal-recessive defect of purine metabolism caused by mutation of the ADSL gene.It can cause severe neurological impairment and diverse clinical manifestations,including epilepsy.CASE SUMMARY Here,we describe a 3-year-old Chinese boy who had both psychomotor retardation and refractory epilepsy.Magnetic resonance imaging showed myelin hypoplasia.Electroencephalography findings supported a diagnosis of epilepsy.Whole-exon sequencing revealed the presence of a novel complex heterozygous mutation in the ADSL gene:The splicing mutation c.154-3C>G and the missense mutation c.71C>T(p.Pro24Leu).Considering the patient’s clinical presentation and genetic test results,the complex heterozygous mutation was predicted to prevent both ADSL alleles from producing normal ADSL,which may have led to ADSL deficiency.Finally,the child was diagnosed with ADSL deficiency.CONCLUSION We identified a novel complex heterozygous mutation in the ADSL gene associated with ADSL deficiency,thus expanding the known spectrum of pathogenic mutations that cause ADSL deficiency.Additionally,we describe epilepsy that occurs in patients with ADSL deficiency.
基金Supported by the Fundamental Research Funds of Health Commission of Sichuan Province,No.17ZD035.
文摘BACKGROUND CYP21A2 gene mutations may all cause reduction or loss of 21-hydroxylase activity,leading to development of congenital adrenal hyperplasia(CAH)with different clinical phenotypes.For families with CAH children,genetic testing of the parents and genetic counseling are recommended to assess the risk of recurrence.CASE SUMMARY We report a case of CAH with a high suspicion before delivery.The risk of the child suffering from CAH during the pregnancy had been underestimated due to the deviation of genetic counseling and genetic testing results.Our report confirmed a CYP21A2 homozygous deletion in this case,CYP21A2 heterozygous deletion in the mother,and a rare 2+0 CYP21A2 deletion in the father.CONCLUSION It is important to analyze the distribution of CYP21A2 gene in the two alleles of parents of children with CAH.
基金supported by the National Natural Science Foundation of China(82460073)the National Key Research and Development Program(2022YFC2503400)+1 种基金the Major Science and Technology Special Plan Project of Yunnan Province(202302AA310045)the Talent Trusteeship Program of Fuwai Yunnan Hospital(2024RCTJ-QN008).
文摘Hypertrophic cardiomyopathy(HCM)is one of the most common inherited cardiovascular diseases,with a global prevalence estimated at 0.2%to 0.5%.1 It is characterized by left ventricular hypertrophy which could not be explained by abnormal loading conditions,and a considerable proportion of patients were accompanied by either resting or inducible left ventricular outflow tract(LVOT)obstruction,leading to impaired cardiac function,mitral regurgitation due to systolic anterior motion(SAM)condition,with subsequent reduced quality of life,adverse clinical outcomes or even sudden death(Supplementary Text 1 online).2 HCM was previously believed to exhibit an autosomal dominant inheritance pattern,typically caused by pathogenic mutations in genes encoding sarcomeric proteins,with MYBPC3 and MYH7 being the most commonly involved genes.3 However,about 60%of all patients test negative for sarcomeric variants,4 suggesting a possible polygenic inheritance pattern in these patients and the contribution of non-genetic factors on disease phenotype(Supplementary Text 2 online).
基金supported by the National Basic Science Center Program of China(82388101)the National Natural Science Foundation of China(82200961 and 82203260)+2 种基金the Science and Technology Commission of Shanghai(20DZ2270800)Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology(2022SKLEKFKT004)China Postdoctoral Science Foundation(2022M720091)。
基金supported by the Guangdong Natural Science Foundation(No.2024A1515010133)the National Key Research and Development Program of China(No.2024YFA0919702)+1 种基金the National Science Foundation of China(No.12426303)the Key Laboratory of Quantitative Synthetic Biology,Chinese Academy of Sciences(No.CKL075).
文摘In the post-genomic era,a central challenge for disease genomes is the identification of the biological effects of specific somatic variants on allosteric proteins and the phenotypes they influence during the initiation and progression of diseases.Here,we analyze more than 38539 mutations observed in 90 human genes with 740 allosteric protein chains.We find that existing allosteric protein mutations are associated with many diseases,but the clinical significance of most mutations in allosteric proteins remains unclear.Next,we develop an ensemble-learning-based model for pathogenic mutation prediction of allosteric proteins based on the intrinsic characteristics of proteins and the prediction results from existed methods.When tested on the benchmark allosteric protein dataset,the proposed method achieves an AUCs of 0.868 and an AUPR of 0.894 on allosteric proteins.Furthermore,we explore the performance of existing methods in predicting the pathogenicity of mutations at allosteric sites and identify potential significant pathogenic mutations at allosteric sites using the proposed method.In summary,these findings illuminate the significance of allosteric mutation in disease processes,and contribute a valuable tool for the identification of pathogenic mutations as well as previously unknown disease-causing allosteric-protein-encoded genes.
